A phase I/II trial of the PD-1 inhibitor retifanlimab (R) in combination with gemcitabine and docetaxel (GD) as first-line therapy in patients (Pts) with advanced soft-tissue sarcoma (STS).
Authors: Evan Rosenbaum, Li-Xuan Qin, Katherine Anne Thornton, Sujana Movva, Benjamin Alexander Nacev, Mark Andrew Dickson, Mrinal M. Gounder, Mary Louise Keohan, Viswatej Avutu, Ping Chi, Ciara Marie Kelly, Jason Earl Chan, Moriah Martindale, Travis Adamson, Olivia Robin McKennan, Joseph Patrick Erinjeri, Robert A Lefkowitz, William D. Tap, Sandra P. D'Angelo
Journal: Journal of Clinical Oncology (2022)

11516 Background: In a phase III trial, GD had similar response and survival rates to doxorubicin when administered as first-line therapy to advanced STS pts. G and D have each demonstrated synergy with PD-1 blockade in pre-clinical or clinical studies. We hypothesized that GD plus R would be safe, tolerable, and have synergistic activity in STS. Methods: This is an ongoing open-label, single-center, phase I/II trial of R (INCMGA00012) combined with GD in pts with treatment-naïve unresectable or metastatic high-grade STS. Herein, we report the phase I results, which included a safety run-in followed by a 3+3 dose de-escalation design. G (900 mg/m 2 ) was administered on days 1 and 8 and D (75 mg/m 2 ) on day 8, in 21-day cycles. R (210 mg IV flat dose on the run-in portion and 375 mg on the dose de-escalation portion) was administered on day 1 of each cycle starting in cycle 2 and continued as monotherapy after completion of 6 cycles of GD. The primary endpoint of the phase I was to determine the recommended phase 2 dose (RP2D) of R plus GD. Secondary endpoints included describing the safety, assessing best overall response rate (ORR) by RECIST 1.1, disease control rate (DCR), and progression-free survival (PFS). Results: Thirteen pts were treated, 7on the run-in and 6 on the de-escalation portion. One pt progressed prior to starting R and was replaced. Median pt age was 53 (range 28 – 74) and 7 were female. Histologies included leiomyosarcoma (n = 6), undifferentiated pleomorphic sarcoma (2), dedifferentiated liposarcoma (2), pleomorphic liposarcoma (1), angiosarcoma (1), and myxofibrosarcoma (1). The Table lists treatment-related adverse events (TRAEs) that occurred in ≥ 20% pts in descending order of frequency. Additional Grade (Gr) 3 TRAEs occurring in 1 pt each, included: infusion reaction, leukopenia, anorectal infection, neutropenia, and pyelonephritis. Gr 3 pyelonephritis was the only dose-limiting toxicity. There were no Gr ≥ 4 TRAEs. One pt (Gr 3 elevated AST/ALT) required corticosteroids and cessation of study therapy. The RP2D was determined to be 375 mg of R plus GD. Twelve pts were evaluable for response. ORR was 17% (1 of 6; 95% CI 1 - 64%) and 50% (3 of 6; 95% CI 19% - 81%) in the run-in and de-escalation cohorts, respectively. DCR was 100% (6 of 6; 95% CI 52 - 100%) and 83% (5 of 6; 95% CI: 36 - 99%). PFS rates at 24 weeks were 60% (95% CI: 29 - 100%) and 44% (95% CI: 17 - 100%). Conclusions: R plus GD was generally safe and well tolerated with no unexpected safety signals to date. The phase II portion evaluating efficacy of R plus GD at the RP2D is ongoing. Clinical trial information: NCT04577014. [Table: see text]